Benzimidazolinone derivatives

ABSTRACT

The compounds, 1-(1-( 3-(10,11-dihydro-5H-diberzo-(a, d)cyclohepten-5-ylidene)propyl)-4-piperidy)-2-benzimidazolinone and 1-(1-(3-(5H-dibenzo(a,d)cyclohepten-5-ylidene)propyl)-4piperidyl)-2 -benzimidazolinone, useful as neuroleptic agents.

TJmTTeeT [1 1 Saudijm et all.

[451 Oct. 22, 1974 [73] Assigneez- Janssen Pharmaeeuticall N.V.,

Beerse, Belgium 221 Filed: 11 mm, 1973 21 A 1.1\1o.;333,sse

[52] US. (:5. 260/24) TC, 424/267 [Sl] Rm. Cl (307ml 49/38 [58} Tieflul of Search 260/240 TC, 293.6, 293.62,

[56] References Cited UNITED STATES PATENTS 3.074.953 [/1963 Davis et ul 260/2943 3,345,364 Ill/I967 Jnnsricn 260/240 1766.174 10/1973 Nukzmishi el al 260/240 TC Primary Examiner-G. Thomas Todd Attorney, Agent, or Firm-Salvatore R. Conte [57] ABSTRACT The corfipdunds, l-{ 1-[3-(10,1 l-dlhxclyo-SH-cliberzo- [a,dlcyclohepten-5-ylidene)pr0pyl]4piperidy}2 benzimidazolinone and 1-{l--[3-(5H-dibenzo[a,d] cyclohepten-S-ylidene)propyl]-4-piperidyl}-2-benzi midazolinone, useful as neuroleprtic agents.

3 (Ilaims, N0 Drawings BENZIMIDAZOLINONE DERIVATIVES DESCRIPTION OF THE INVENTION This invention relates to novel benzimidazolinone derivatives which may be structurally represented by the formula:

wherein the dotted line represents an optional double bond. Without such double bond, the benzimidazolinone derivative is 1- {1-[3-( 10,1 l-dihydro-SH- dibenzola,d]cyclohept en--ylidene)-propyl] 4- piperidyl}-2-benzimidazolinone; and with the double bond, the benzimidazolinone derivative is l-{-- -[3-(5H-dibenzo[a,d]cyclohepten5-ylidene)propyl]- 4-piperidyll-2-benzimidazolinone.

The subject compounds (I) are prepared by reacting an appropriate dibenzo[a,d]cyc1oheptylidene of formula (ll where X is a reactive ester of the corresponding alcohol, e.g., chloro, bromo, mesylate, tosylate and the like, preferably chloro or bromo, with 1-(4- piperidyl)-2-benzimidazolinone (111). This condensation reaction is conveniently conducted in an=inertorganic solvent such as, for example, an aromatic hydrocarbon e.g., benzene, toluene, xylene and the like; a lower alkanol, e.g., methanol, ethanol, n-butanol and the like; a ketone, e.g., 4-methyl-2-pentanone, butanone, and the like; an ether, e.g., dioxane, diethyl ether and the like; dimethylformamide (DMF); nitroben zene; and the like. The addition of an acid acceptor, i.e., an appropriate base such as, for example, an alkali metal carbonate or bicarbonate, or an organic tertiary amine, such as, for example, a trialkylamine, e.g., triethylamine, tributylamine and the like, or a heterocyclic amine, e.g., pyridine, quinoline and the like, may be utilized to bind the acid that is liberated during the course of the reaction. The amount of acid acceptor that may be employed is not critical, but, for optimum conditions, the theoretical number of moles of liberated acid can easily be calculated from the quantities of reactants employed and. thus, the corresponding amount of acid acceptor that need be employed can readily be determined. The presence of catalytic amounts of potassium iodide is also desirable when X is halo. Elevated temperatures may be employed to enhance the rate of reaction.

The compounds of formula (I) have been found to (II) (III) 3,438,991), and of certain benzimidazolinones, e .g. pimozide (see US. Pat. No. 3,196,157) and of the 4-aryl-4hydroxypiperidines in US. Pat. No. 3,575,990. Althoughthe subject compounds are qualitatively similar in neuroleptic activity to haloperidol, they differ significantly from the latter in their longer duration of action, similar to saidpimozide and to said 4-aryl-4-hydroxypiperidines.

Neuroleptic drugs are known to block apomorphineinduced vomiting in dogs. In the anti-apomorphine test [see Method 1" in Janssen, P.A.J., et al., Arzneim.- Forsch, 15, 1,196 (1965)], the compound to be tested is given orally followed at different timelintervals thereafter by the standard dose of apomorphine (0.31 mg/kg s.c.) which will induce vomiting inuntreated dogs. Anti-apomorphine activity-is demonstrated .with the compounds (I) at oral dose levels as low as 0.005mg/kg and at ED values of about 0.02- 1.0 mg/kg orally. The

ED value (in mg/kg) is the oral dose'level of the tested compound protecting 50% of'the animals from emesis. In Table l, the ED values and the duration of activity of the compounds described herein are given.

the oral dose levels at which the subject;compounds I protectthe rats againstthe amphetamine-induced agi tation and chewing.

TABLE 1 Amphetamine Compound Anti-apomorphine test antagonism of Example in dogs (oral) in rats (oral) ED Duration ED. 1 0.46 mg/kg 20' hours 2.5 mg /kg II 0.40 mg/kg 35' hours 2.5 mg/kg The following examples are intended to illustrate, but,

not to limit, the scope of the present invention; Unless otherwise stated, all partsare by weight.

EXAMPLE I A mixture of 1.63 parts of 5-(3 -bromopropylidene)- 10,1 1-dihydro-5H-dibenzo[a,d]cycloheptane, 1.09

parts of l-(4-piperidyl)-2 benzimidazolinone, 0.8 parts possess central nervous system (CNS) depressant activ- 5 of anhydrous sodium carbonate and 7.5 parts of diity similar to the neuroleptic activity of butyrophenones, for example, haloperidol (see US. Pat. No.

methylformamide is stirred and heated at C for 3 hours. The reaction mixture is cooled, filtered over hyflo, and upon dilution of the filtrate with water, the product, 1-{1-[3-(10,1 l-dihydro-SH- dibenzo[a,d]cyclohepten--ylidene)propy11-4- piperidyll-2-benzimidazolinone, is crystallized. It is filtered off, washed with water.and recrystallized from ethyl acetate, yielding 1-{1-[3-(10,1l-dihydro-SH- dibenzo[a,dlcyclohepten-S-ylidene)propyl]-4- piperidyl}-2-benzimidazolinone hydrate; mp. 108.5C.

EXAMPLE I] A mixture of 1.37 parts of 5-(3-bromopropy1idene)- 5H-dibenzo[a,d]cycloheptene, 0.87 parts of 1-(4- piperidyl)-2-benzimidazolinone, 0.64 parts of sodium carbonate and 5 parts of dimethylformamide is stirred for 3 hr. 30 min. in an oil-bath at 110C. The reaction mixture is cooled, filtered and the filtrate is diluted with water. The precipitated product is filtered off, washed with water, dried and taken up in chloroform. The chloroform solution is purified by columnchromatography, using a mixture of chloroform and Spercent of methanol. The pure fractions are collected and the solvent is evaporated. The residue is crystallized from ethyl acetate. The product is filtered off freedom recrystallized from ethanol yielding after drying in vacuo at C, 1{l-[3-(5H-dibenzo[a,d]-

. cyclohepten-S-ylidene)propyl]-4-piperidyl}-2-benzimidazolinone; mp. 217.8C.

We claim:

1. A benzimidazolinone derivative having the formula:

P0405? UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3, 6, 3 Dated October 22,1

Inventor(s) Willem Soudijn, Ineke Van wijngaarden, Paul Adriaan Jan Janssen It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

In the Abstract, line 1, "diberzo" should read dibenzo In Column line 2, "freedom" should read and Signed and sealed this 18th day of March 1975.

(SEAL) Attest:

C. MARSHALL DANN RUTH C. MASON Commissioner of Patents Attesting Officer and Trademarks 

1. A BENZIMIDAZOLINONE DERIVATIVE HAVING THE FORMULA:
 2. 1-(1-(3-(10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5-ylidene)propyl)-4 -piperidyl)-2-benzimidazolinone hydrate.
 3. 1-(1-(3-(5H-dibenzo(a,d)cyclohepten-5-ylidene)-propyl)-4-piperidyl)-2 -benzimidazolinone. 